Dose-Response Models INDEX

Additivity and no interactions. Additivity concepts that explain a shared adverse effect across chemicals include dose or concentration addition, which assumes chemicals share a common toxic MOA, and RA, which assumes chemicals act by toxicologically (and thus also statistically) independent MOA. There is also a body of research on the use of statistical dose-response modeling of empirical data to examine the joint toxic action of defined mixtures where the claim is that MOA assumptions are not necessary (Gennings et al. 2005). Dose addition methods scale the component doses for relative toxicity and estimate risk using the total summed dose, for example, using relative potency factors (RPFs), toxicity equivalency factors (TEFs), or a hazard index (HI). In contrast, RA (also named independent action ) is... 

Assessment of Human Health Mixture RfD/RfC Hazard Quotient Hazard Index Dose-Response Modeling Cancer Slope Factors Epidemiological Measures Comparative Potency... 

Figure 5.9. Dose-response profile in a population. (A) Relationship between responding patients, expressed as percentage of individuals, and plasma drug concentrations. With increasing drug concentration, the proportion of patients who derive therapeutic benefit, without concentration-limited side effect peaks, and then declines. (B) A schematic representation of dose-response curves. Typical therapeutic and lethal responses at indicated doses are evaluated in animal models to estimate therapeutic index, TI. ED50, effective dose needed to produce a therapeutic response in 50% of animals, exhibiting therapeutic response LD50, effective dose needed to produce lethal effects in 50% of animals.

EPA recommends three approaches (1) if the toxicity data on mixture of concern are available, the quantitative risk assessment is done directly form these preferred data (2) when toxicity data are not available for the mixture of concern, data of a sufficiently similar mixture can be used to derive quantitative risk assessment for mixture of concern and (3) if the data are not available for both mixture of concern and the similar mixture, mixture effects can be evaluated from the toxicity data of components. According to EPA, the dose-additive models reasonably predict the systemic toxicity of mixtures composed of similar (dose addition) and dissimilar (response addition) compounds. Therefore, the potential health risk of a mixture can be estimated using a hazard index (HI) derived by summation of the ratios of the actual human exposure level to estimated maximum acceptable level of each toxicant. A HI near to unity is suggestive of concern for public health. This approach will hold true for the mixtures that do not deviate from additivity and do not consider the mode of action of chemicals. Modifications of the standard HI approach are being developed to take account of the data on interactions. 

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